Pharmacokinetic–Pharmacodynamic Modeling of Enrofloxacin Against Escherichia coli in Broilers

Abstract

The purpose of the present study was to establish a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach for the dosage schedule design and decreasing the emergence of drug-resistant bacteria. The minimal inhibitory concentration (MIC) of 929 Escherichia coli isolates from broilers to enrofloxacin and ciprofloxacin was determined following CLSI guidance. The MIC50 was calculated as the populational PD parameter for enrofloxacin against E. coli in broilers. The 101 E. coli strains with MIC closest to the MIC50 (0.05 μg/mL) were submitted for serotype identification. The 13 E. coli strains with O and K serotype were further utilized for determining pathogencity in mice. Of all the strains tested, the E. coli designated strain Anhui 112 was selected for establishing the disease model and PK/PD study. The PKs of enrofloxacin after oral administration at the dose of 10 mg/kg body weights (BW) in healthy and infected broilers was evaluated with high-performance liquid chromatography (HPLC) method. For intestinal contents after oral administration, the peak concentration (Cmax), the time when the maximum concentration reached (Tmax), and the area under the concentration-time curve (AUC) were 21.69–31.69 μg/mL, 1.13–1.23 h, and 228.97–444.86 μg h/mL, respectively. The MIC and minimal bactericidal concentration (MBC) of enrofloxacin against E. coli (Anhui 112) in Mueller–Hinton (MH) broth and intestinal contents were determined to be similar, 0.25 and 0.5 μg/mL respectively. In this study, the sum of concentrations of enrofloxacin and its metabolite (ciprofloxacin) was used for the PK/PD integration and modeling. The ex vivo growth inhibition data were fitted to the sigmoid Emax (Hill) equation to provide values for intestinal contents of 24 h area under concentration-time curve/MIC ratios (AUC0–24 h/MIC) producing, bacteriostasis (624.94 h), bactericidal activity (1065.93 h) and bacterial eradication (1343.81 h). PK/PD modeling was established to simulate the efficacy of enrofloxacin for different dosage regimens. By model validation, the protection rate was 83.3%, demonstrating that the dosage regimen of 11.9 mg/kg BW every 24 h during 3 days provided great therapeutic significance. In summary, the purpose of the present study was to first design a dosage regimen for the treatment E. coli in broilers by enrofloxacin using PK/PD integrate model and confirm that this dosage regimen presents less risk for emergence of floroquinolone resistance.

Clinical Efficacy and Residue Depletion of 10% Enrofloxacin Enteric-Coated Granules in Pigs

“…The PK and residue of ENR in the serum of goats, pigs, calves, horses, sheep, and broilers have already been investigated in previous reports (Kaartinen et al, 1995; Giguère et al, 1996; Mckellar et al, 1997, 1999; Anadón et al, 1999; Elmas et al, 2001; Sang et al, 2015; Haag et al, 2016). However, most ENR products were difficult to feed in forage or water because of poor palatability.…”

Virulence and transcriptome profile of multidrug-resistant Escherichia coli from chicken

“…These MDR organisms carry antibiotic-resistant genes with the potential to spread to other populations 28 . The abundant use of antibiotics in poultry farms has been associated with treatment failure and the development of antibiotic resistance itself 29 . A study showed that E. coli from poultry in China were resistant to at least 18 different antibiotics 16 .…”

“…Clinical pathogenic E. coli isolates (n = 929) were previously collected from cases of broilers colibacillosis and initially screened for resistant to ciprofloxacin 29 . Of the 929 isolates, 45 strains with high MICs ( ≥ 16 µg/mL) against ciprofloxacin were selected for this study, due to the fact that chicken is the source of ciprofloxacin-resistant human E. coli 96 – 98 .…”

Pharmacokinetics of tilmicosin in healthy pigs and in pigs experimentally infected withHaemophilus parasuis

“…The PK features of TIL have already been studied in many species, including broiler chickens [ 23 ], equine [ 4 ], swine [ 25 ], goats [ 22 ], and rats [ 18 ]; however, PK investigations of TIL in infected animals are quite few. The PK profiles of a drug can be influenced by the pathophysiological changes during an infection, and PK parameters in infected animals are more close to the clinical conditions [ 15 24 ]. As previously reported, physiological and biochemical differences such as body temperature, plasma protein binding ratio, blood pressure, anemia, and liver function in healthy and diseased animals can result in changes to a drug's PK profile and parameters [ 28 ].…”